Targeting the Grb2 cSH3 domain: Design, synthesis and biological evaluation of the first series of modulators.

Bioorganic chemistry 2023 Sep

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Growth factor receptor bound protein 2 (Grb2) is an adaptor protein featured by a nSH3-SH2-cSH3 domains. Grb2 finely regulates important cellular pathways such as growth, proliferation and metabolism and a minor lapse of this tight control may totally change the entire pathway to the oncogenic. Indeed, Grb2 is found overexpressed in many tumours type. Consequently, Grb2 is an attractive therapeutic target for the development of new anticancer drug. Herein, we reported the synthesis and the biological evaluation of a series of Grb2 inhibitors, developed starting from a hit-compound already reported by this research unit. The newly synthesized compounds were evaluated by kinetic binding experiments, and the most promising derivatives were assayed in a short panel of cancer cells. Five of the newly synthesized derivatives proved to be able to bind the targeted protein with valuable inhibitory concentration in one-digit micromolar concentration. The most active compound of this series, derivative 12, showed an inhibitory concentration of about 6 μM for glioblastoma and ovarian cancer cells, and an IC50 of 1.67 for lung cancer cell. For derivative 12, the metabolic stability and the ROS production was also evaluated. The biological data together with the docking studies led to rationalize an early structure activity relationship. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Marianna Bufano, Michela Puxeddu, Marianna Nalli, Giuseppe La Regina, Angelo Toto, Francesca Romana Liberati, Alessio Paone, Francesca Cutruzzolà, Domiziana Masci, Chiara Bigogno, Giulio Dondio, Romano Silvestri, Stefano Gianni, Antonio Coluccia. Targeting the Grb2 cSH3 domain: Design, synthesis and biological evaluation of the first series of modulators. Bioorganic chemistry. 2023 Sep;138:106607